Expanding the synthesizable multisubstituted benzo[b]thiophenes via 6,7-thienobenzynes generated from o-silylaryl triflate-type precursors

Various 2,3-disubstituted 6,7-thienobenzynes have been efficiently generated from the corresponding o-silylaryl triflate-type precursors by activation with fluoride ions. The method has expanded the scope of synthesizable multisubstituted benzothiophenes, including those with various heteroatom substituents, and can be applied to the synthesis of EP4 antagonist analogs.


Introduction
Benzo [b]thiophene is one of the structural units frequently found in molecules applied in various research elds, including medicinal chemistry and materials science. 1-3 Although multisubstituted benzothiophenes are promising compounds as pharmaceutical and organic material candidates, their synthetic approaches are limited. 4 To improve this situation, we previously reported a facile method to prepare various tetrasubstituted benzothiophenes via thienobenzyne intermediates such as I (Fig. 1A). 5 Thienobenzynes I were efficiently generated from o-iodoaryl triate-type precursors by treatment with a silylmethyl Grignard reagent at À78 C, rendering a diverse range of tetrasubstituted benzothiophenes easily available. 6 We considered that the use of o-silylaryl triate-type thienobenzyne precursors would further expand the scope of the synthesizable benzothiophenes (Fig. 1B). This is because generation of arynes from this type of precursor has been generally achieved under mild conditions using a basic activator such as the uoride ion. 7-9 Indeed, a wide range of aromatic compounds have become easily available via the transformation of arynes generated from o-silylaryl triate-type precursors. Herein, we report the synthesis of o-silylaryl triate-type 6,7-thienobenzyne precursors, the generation of aryne species from these precursors, and the application of the method to the synthesis of various benzothiophenes including potent analogs of a prostaglandin E receptor subtype 4 (EP4) antagonist.

Synthesis of thienobenzyne precursors
Similar to our previous synthesis of o-iodoaryl triate-type 6,7thienobenzyne precursors, o-silylaryl triate-type precursors 2ad were successfully prepared from the corresponding 2,3disubstituted 6-hydroxybenzo [b]thiophenes 1a-d (Schemes 1 and 2). 5 Benzothiophenes 2a-c were prepared from 6-hydroxybenzothiophenes 1a-c according to the facile synthetic method for o-silylaryl triates from phenols as reported by Garg and coworkers; carbamate formation using isopropyl isocyanate, regioselective C-silylation via ortho-lithiation, removal of the directing group, and triylation (Scheme 1). 10 Although preparation of benzothiophene 2d, bearing a chloro and an amide group, from phenol 1d by the same method was unsuccessful at the step of C-silylation via ortho-lithiation, the C-  product was obtained by an alternative method (Scheme 2). 11 Thus, regioselective iodination of phenol 1d with a morpholine-iodine complex, followed by O-silylation and treatment with the turbo Grignard reagent to promote the iodine-magnesium exchange reaction and subsequent retro-Brook rearrangement via the anionic intermediate II, afforded o-silylphenol 4, leaving the chloro and amide groups untouched. Finally, triylation of 4 afforded the desired 2d. 12,13 Performing the retro-Brook rearrangement and subsequent O-triylation in one-pot procedure 12a afforded 2d in 13% yield.

Optimization of the reaction conditions for generation of thienobenzynes
The efficient conditions for generating 6,7-thienobenzyne were screened for the reaction between precursor 2a and azide 5a in tetrahydrofuran (THF) at room temperature, which revealed that various uoride sources or cesium carbonate with 18crown-6 were effective as an activator (Table 1). For example, the activation of 2a with potassium uoride in the presence of 18crown-6 afforded the desired cycloadduct 6a with a small amount of regioisomer 6a 0 (entry 1). The regioselectivity was slightly lower than that observed in the reaction using oiodoaryl triate-type 6,7-thienobenzyne precursor probably because the reaction triggered by silicate formation was conducted at a higher temperature. Tetra(n-butyl)ammonium diuoro(triphenyl)silicate and tetra(n-butyl)ammonium uoride also served as good activators without any additives (entries 2 and 3). While using potassium uoride alone was ineffective (entry 4), 2a was efficiently activated with cesium uoride, resulting in the highest combined yield of cycloadducts 6a and 6a 0 (entry 5). Considering that the generation of benzyne from o-(trimethylsilyl)phenyl triate with cesium uoride in THF was reported as inefficient, 9a this result suggests that thienobenzyne precursor 2a is more easily activatable than the simple o-silylphenyl triate. Decreasing the amount of azide 5a to 2.0 equiv. slightly lowered the yield of 6a/6a 0 (entry 6). In addition, 6,7thienobenzyne was also generated efficiently under uoride-free conditions using cesium carbonate and 18-crown-6 (entry 7). 9a

Synthesis of various multisubstituted benzothiophenes via thienobenzynes
Under the optimal conditions, various arynophiles reacted efficiently with thienobenzyne generated from 2a to afford multisubstituted benzothiophenes in high yields (Fig. 2). These include cycloadducts 7, 8, 9/9 0 , and 10 obtained from the reactions with 2,5-dimethylfuran, N-phenylpyrrole, N-(tert-butyl)-aphenylnitrone, and 1,1-dimethoxyethylene, respectively. The nucleophilic addition of morpholine to the 6,7-thienobenzyne also took place, affording 6-morpholinobenzothiophene 11 as the major product. The regioselectivity observed using unsymmetrical arynophiles and the nucleophile showed similar trends to their reactions with the same thienobenzyne species generated from the o-iodoaryl triate-type precursor. 5 An abundance of utilizable transformations is a great advantage of using o-silylaryl triates as aryne precursors over the other types. Indeed, the utility of o-silylaryl triate-type 6,7thienobenzyne precursor was demonstrated through several unique transformations that we recently developed (Fig. 3). 14 For example, the Michaelis-Arbuzov-type reaction of the  thienobenzyne generated from 2a with alkoxyphosphine 12 proceeded smoothly, affording a high yield of arylphosphonic diamide 13 as the sole product (Fig. 3A). 14a Furthermore, difunctionalizations of the thienobenzyne intermediate with sullimine 14, 14b sulfoximine 16, 14c and sulfoxide 18 14d resulted in the selective formation of thioaminated or oxythiolated benzothiophenes 15/15 0 , 17, and 19, respectively, which are difficult to prepare by conventional methods (Fig. 3B). The yields of thioaminated products 15/15 0 and 17 were improved under modied conditions wherein the reactions were carried out at a higher temperature in 1,4-dioxane. Various 2,3-disubstituted 6,7-thienobenzynes were also generated from precursors 2b-d (Fig. 4). The reactions of these thienobenzynes with azide 5a afforded triazole-fused 3-methyl-2-phenyl-, 2-methylsulfanyl-3-triuoromethyl-, and 3-chloro-2-(dimethylamino)carbonylbenzothiophene derivatives 6b/6b 0 , 6c, and 6d/6d 0 , respectively, in a regioselective manner. Cycloadduct 6c was obtained as a single isomer along with complex mixtures of side-products probably due to the effect of the electron-withdrawing triuoromethyl group. A similar trend was observed in our previous study, 5 wherein 6c was obtained without formation of the regioisomer using o-iodoaryl triatetype aryne precursor activated with a silylmethyl Grignard reagent.

Synthesis of the analogs of an EP4 antagonist
The utility of this method was demonstrated in the facile diversication of the benzo-moiety of the EP4 antagonist 20a developed by Li and coworkers (Scheme 3). 15 The analogs 20bd with methyltriazole-fused, benzo-fused, or morpholinosubstituted benzothiophene structure, respectively, were easily prepared via the reactions of the thienobenzyne intermediate generated from 2d with (trimethylsilyl)methyl azide, furan, and morpholine, affording adducts 21a-c as the major products. According to the modied method reported previously for the derivatization of 21a to 20b, 5 EP4 antagonist analogs 20c and 20d were prepared by the Suzuki-Miyaura cross-coupling, the Mitsunobu-type C-N bond formation followed by treatment with hydrazine, and amidation. Evaluations of the EP4 receptor binding affinities showed that benzo-fused analog 20c (K i ¼ 0.18 mM) is a potent EP4 antagonist comparable to the original compound 20a (K i ¼ 0.25 mM), while methyltriazole-fused analog 20b (K i ¼ 0.47 mM) and morpholino-substituted analog 20d (K i ¼ 0.70 mM) are slightly weaker antagonists than 20a. 16 This result suggests a possibility for developing more potent EP4 antagonists by further modication of the benzo-moiety of 20a.

Conclusions
This study showed that 7-silyl-6-triyloxybenzo [b]thiophenes served as useful precursors of 6,7-thienobenzynes, thus expanding the range of synthesizable multisubstituted benzothiophenes. The utility of the method was demonstrated for the synthesis of various heteroatom-substituted benzothiophenes and the facile structural diversication of an EP4 antagonist that resulted in identication of a potent analog.

Conflicts of interest
There are no conicts to declare.